The pulmonary circulation is a simple vascular bed: a low resistance, high flow, largely passive circuit which, nevertheless, is capable of balancing perfusion to ventilation by hypoxic vasoconstriction. With regard to the hemodynamics of the actual gas exchange vessels, however, there are many unexplored areas as well as areas of controversy. In this proposal, we will investigate the fundamental ways in which perfusion of the gas exchange vessels is regulated by directly studying the pulmonary microcirculation using in vivo video microscopy, a method we have developed during the last three decades. Based on pilot data supporting each concept, we will test aspects of the following working hypotheses: (1) the constant flow switching between capillaries in individual alveolar walls is caused by both active and passive components, (2) "non-muscular" precapillary arterioles and post-capillary venules are capable of constriction, (3) small muscular arterial impedance is regulated by sympathetic nerve stimulation. We have developed new methods to test these ideas including software for statistical analysis of capillary perfusion patterns, an image enhancing system for accurate measurement of microvascular diameters, a high-output laser light source, and the non- traumatic fluorescent labeling of red blood cells. Utilizing these techniques, we will explore our finding that the perfusion pattern of the pulmonary capillaries is in constant flux within a single alveolar wall, even when upstream vascular pressures and flows are held constant. Experiments are designed to investigate whether the capillary perfusion pattern alterations are regulated by constriction or are the passive result of a particulate fluid crossing an extremely complex capillary network. We will investigate whether the long-term pattern fluctuations are fractal in nature. Additional studies will determine to what extent the variable perfusion pattern is the result of leukocytes being transiently trapped in the pulmonary capillaries. Our pilot studies also demonstrate that the perfusion of a single acinus is considerably heterogeneous suggesting that ventilation-perfusion balance may be necessary within an acinus. Small arterioles and venules, therefore, might have an active role in ventilation-perfusion balance. Indeed our preliminary work shows both precapillary arterioles and post-capillary venules to be capable of vasoconstriction, suggesting the unsuspected possibility of finely-tuned flow regulation within the acinar functional unit of the lung. Finally, we will study the effects of sympathetic nerve stimulation on muscular pulmonary arteries and record the resultant alterations in perfusion of the gas exchange vessels. Any demonstrable flow alterations could be of physiologic import, for the function of this part of the nervous system on pulmonary perfusion has remained enigmatic. We believe these proposed investigations of the pulmonary microcirculation offer a unique opportunity for exploring the fundamental ways in which perfusion of the gas exchange vessels is regulated.